Process for preparing tetrazol-5-yl substituted benzopyran compounds

ABSTRACT

A process for preparing substituted benzopyran derivatives which comprises a final step cyclisation of the corresponding open-chain intermediates.

The present invention relates to a new process for preparing certainsubstituted benzopyran compounds, intermediates useful in the process,and to a process for the preparation of the intermediates.

Substituted benzopyran compounds are known in the art. For example, EP 0173 516-A discloses a class of substituted benzopyran compounds whichare described as compounds having activity as leukotriene antagonistsand useful in therapy in the treatment of, for example, diseases inducedby leukotrienes and 5-α-reductase.

The present invention relates to a new process for preparing certain ofthe benzopyran compounds described in EP 0 173 516-A, and in particularprovides an efficient route to the compounds in which far fewer reactionsteps are involved than has hitherto been described. A reduction in thenumber of reaction steps involved in preparing end products generallyresults in a much more efficient and cost-effective route than oneinvolving large n-mbers of steps.

The present invention therefore provides in a first aspect a process forpreparing a compound of structure (I): ##STR1## in which, R¹ is C₁₋₂₀alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, or a group of structure: ##STR2##each of which may be substituted by one or two substituents selectedindependently from C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl or C₂₋₂₀ alkynyl, up to 5carbon atom(s) of which may optionally be replaced by oxygen atom(s),sulphur atom(s), halogen atom(s), nitrogen atom(s), benzene ring(s),thiophene ring(s), naphthalene ring(s), carbocychc ring(s) of from 4 to7 carbon atom(s), carbonyl group(s), carbonyloxy group(s), hydroxygroup(s), carboxy group(s), azido group(s) and/or nitro group(s);

R² is hydrogen or C₁₋₆ alkyl;

R³ is hydrogen, halogen, hydroxy, nitro, a group of general formula--COOR⁴ (wherein R⁴ represents hydrogen or C₁₋₆ alkyl), C₁₋₆ alkyl, C₁₋₆alkoxy or C₁₋₆ alkylthio;

A is a single bond or a methylene, ethylene, trimethylene,tetramethylene, vinylene, propenylene, butenylene, butadienylene orethynylene group optionally being substituted by one, two or three C₁₋₁₀alkyl and/or phenyl group(s); and

X is oxygen or sulphur;

or a salt, solvate or hydrate thereof, which comprises cyclisation of acompound of structure (II) ##STR3## or a salt, hydrate or solvatethereof, in which R¹, R², R³, A and X are as described for structure(I), and optionally thereafter forming a salt, solvate or hydratethereof.

Suitably, R¹ is C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, or a group ofstructure: ##STR4## each of which may be substituted by one or twosubstituents selected independently from C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl orC₂₋₂₀ alkynyl, up to 5 carbon atom(s) of which may optionally bereplaced by oxygen atom(s), sulphur atom(s), halogen atom(s), nitrogenatom(s), benzene ring(s), thiophene ring(s), naphthalene ring(s),carbocyclic ring(s) of from 4 to 7 carbon atom(s), carbonyl group(s),carbonyloxy group(s), hydroxy group(s), carboxy group(s), azido group(s)and/or nitro group(s).

Preferably R¹ is a group of structure (i) substituted or unsubstitutedby one or two substituents selected independently from C₁₋₂₀ alkyl,C₂₋₂₀ alkenyl or C₂₋₂₀ alkynyl, up to 5 carbon atom(s) of which mayoptionally be replaced by oxygen atom(s), sulphur atom(s), halogenatom(s), nitrogen atom(s), benzene ring(s), thiophene ring(s),naphthalene ring(s), carbocyclic ring(s) of from 4 to 7 carbon atom(s),carbonyl group(s), carbonyloxy group(s), hydroxy group(s), carboxygroup(s), azido group(s) and/or nitro group(s).

More preferably R¹ is a group of structure (i) substituted in the paraposition of the ring by a single substituent selected from the above, inparticular R¹ is a group of structure ##STR5##

Suitably, R² is hydrogen or C₁₋₆ alkyl; preferably R² is hydrogen.

Suitably, R³ is hydrogen, halogen, hydroxy, nitro, a group of generalformula --COOR⁴ (wherein R⁴ represents hydrogen or C₁₋₆ alkyl) or C₁₋₆alkyl, C₁₋₆ alkoxy or C₁₋₆ alkylthio. Preferably R³ is hydrogen.

Suitably A is a single bond or a methylene, ethylene, trimethylene,tetramethylene, vinylene, propenylene, butenylene, butadienylene orethynylene group optionally being substituted by one, two or three C₁₋₁₀alkyl and/or phenyl group(s). Preferably A is a single bond.

Suitably, the cyclisation of the compound of structure (II) is carriedout in the presence of an acid. For example, the cyclisation can becarried out in the presence of sulphuric acid, in methanol or in aceticacid as the solvent medium. Preferably the reaction is carried out in amethanol/tetrahydrofuran solvent mixture in the presence of hydrochloricacid. Alternative acid/solvent conditions will be apparent to thoseskilled in the art and include, for example, acids such as hydrobromicor hydroiodic acid, perchloric acid or p-toluene sulphonic acid, andLewis Acids for example aluminium trichloride, in suitable solvents suchas water, C₁₋₄ alkanols such as ethanol or methanol, and unsaturatedcarbocyclic hydrocarbons such as benzene or toluene.

It is to be noted that, although for the sake of convenience structure(II) is represented as the `di-keto` form, the compounds of structure(II) can exist also in the `kete-enol` form and in the `cyclic hydroxychromanone` form (IIB) ##STR6## It is intended that structure (II)encompasses all of the tautomeric forms of the compounds of structure(II).

In a preferred aspect there is therefore provided a process for thepreparation of a compound of structure (IA) or a salt, solvate orhydrate thereof: ##STR7## which comprises cyclisation of a compound ofstructure (IIA) or a salt, solvate or hydrate thereof: ##STR8## andoptionally thereafter forming a salt, solvate or hydrate thereof. Mostpreferably, the cyclisation is carried out in the presence ofhydrochloric acid in methanol/tetrahydrofuran as solvent,

As for compounds of structure (II), the compounds of structure (IIA)can, of course, exist in the corresponding keto-enol and cyclicchromanone forms, each of which are intended to be encompassed by thestructure (IIA).

The compounds of structure (II) (and in particular structure (IIA)) arenovel and form a further aspect of the invention. The compounds ofstructure (II) can be prepared by the reaction of a compound ofstructure (III) ##STR9## in which R¹, R², R³, A and X are as describedfor structure (I) in claim 1 with a compound of structure (IV) or a saltthereof ##STR10## in which Z is an activated leaving group.

Suitably, activated leaving groups Z include, for example, activatedamides of structure N(R⁵)(OR⁵) in which R⁵ is C₁₋₆ alkyl, halogengroups, groups of structure R⁶ O, R⁶ S or R⁶ SO₂ O in which R⁶ is C₁₋₆alkyl, optionally substituted phenyl or optionally substituted phenylC₁₋₆ alkyl, or groups of structure ##STR11## in which R⁷ is C₁₋₆ alkyl,optionally substituted phenyl or optionally substituted phenyl C₁₋₆alkyl, and each group X is, independently, oxygen or sulphur. PreferablyZ is R⁶ O.

Suitably, R⁶ is C₁₋₆ alkyl, optionally substituted phenyl or optionallysubstituted phenyl C₁₋₆ alkyl. Preferably, R⁶ is C₁₋₆ alkyl, forexample, methyl, ethyl, i-butyl or t-butyl; most preferably R⁶ is ethyl.

Suitably, the reaction is carried out in an organic solvent such as forexample, dimethylformamide, ethereal solvents such as tetrahydrofuran,toluene or benzene, hexanes or C₁₋₆ alkanols such as methanol orethanol, in the presence of a base, for example an alkali metal alkoxidesuch as potassium t-butoxide, sodium methoxide or potassium methoxide,hydrides such as sodium hydride, or an amide base such as potassiumamide or sodium amide. Preferably, the reaction is carried out intetrahydrofuran as a solvent in the presence of sodium methoxide as abase.

The process for preparing the compounds of structure (II) is novel andforms a further aspect of the invention. In particular, the process ispreferred to be used in the preparation of the compounds of structure(IIA) by reaction of the following compounds of structure (IIIA) and acompound of structure (IVA) or a salt thereof, in the presence of sodiummethoxide in tetrahydrofuran as a solvent: ##STR12##

The compounds of structure (III) and (IV) are prepared from commerciallyavailable starting materials by standard techniques as hereinafterdescribed. For example, the preparation of compounds of structure (III)is described in EP 0 173 516-A. Compounds of structure (IV), for examplein which Z is R⁶ O, can be prepared from sodium azide and an appropriatealkyl cyanoformate such as ethyl cyanofomate by known methods or fromtetrazole-5-carboxylic acid disodium salt (commercially available) byreaction with the appropriate alloyl, aryl or arylalkyl haloformate, forexample, ethylchlorofomate or isobutylchlorofomate. The preparation ofcompounds of structure (IV) from the correspondingtetrazole-5-carboxylic acid disodium salt is novel and forms a stillfurther aspect of the invention. It is to be noted that the compounds ofstructure (IV) can be prepared and then isolated before reaction withappropriate compounds of structure (HI), or can be prepared `in situ`and further reacted with the compounds of structure (III) without priorisolation.

The present invention is in particular useful in the preparation of thecompounds of structure (IA) beginning from compounds (ILIA) and (IVA) toform the intermediates of structure (IIA) which undergo cyclisationunder the conditions described herein to form the desired product. Thecompounds of structure (II) can be isolated from the reaction mixturebefore cyclisation to the compounds of structure (I) or alternatively,as described in the examples, the reaction between compounds ofstructures (III) and (IV) followed by the cyclisation of the compoundsof structure (II) so formed can be carried to completion in `one pot`,that is to say without the isolation of the intermediates so formed.

The following examples serve to illustrate the invention. Temperaturesare recorded in degrees Celsius (°C.).

EXAMPLES

1. Preparation of Ethyl-1H-Tetrazole-5-Carboxylate

Trifiuoroacetic acid (24.47 g, 0.21M) was added dropwise over 0.5 hrunder nitrogen to a stirred suspension of sodium azide (12.59 g, 0.19M)in 2,6-lutidine (100 ml) at 8° to 12°. After stirring for 7 minutesethyl cyanoformate (20.4 g, 0.20M) was added in one portion. The mixturewas heated and stirred at 75° for 6 hours and then, after cooling,stirred at 20° for 16 hr. After cooling to 10° the mixture was added toice (250 g) and 11 molar hydrochloric acid (100 ml) keeping thetemperature below 20°. The product was extracted into ethyl acetate(1×250, 1×200, 2×100 ml) and the combined extracts dried over magnesiumsulphate. After evaporation of the solvent under reduced pressure theoily product (38.22 g) was taken up in ether (50 ml) and hexane (25 ml)added. Storage at 4° for 2-3 days produced crystallineethyl-1H-tetrazole-5-carboxylate that was filtered off, washed withchilled ether, and air dried, 14.12 g (52.6% yield), m.p. 88°-93°.

NMR: (270 MHz, solution in CDCl₃) δ13.6-13.8 (s, 1H); 4.6-4.5 (q, 2H);1.5-1.4 (t, 3H).

Workup variation

On a larger scale (83.4 g sodium azide) the reaction was worked updifferently in order to prevent the liberation of any hydrazoic acid.

After stirring at 75° and 20° a solution of sodium nitrite (63 g) inwater (300 ml) was added over 10 minutes at 20° to 30°. The mixture wasstirred at 20°-25° for 20 minutes and then a chilled mixture of water(1.5 L) and 11 molar hydrochloric acid (690 ml) added keeping thetemperature between 25° and 30°. The product was then extracted intoethyl acetate and crystallised as described above.

2. Preparation of i-Butyl-1H-Tetrazole-5-Carboxylate

To a stirred suspension of tetrazole-5-carboxylic acid disodium salt(15.8 g, 0.1 mol) in dimethylformamide (100 ml) under a nitrogenatmosphere at 5° was added isobutyl chloroformate (13.6 g, 13 ml, 0.1mol) dropwise over 15 minutes. The mixture was stirred at 5°-10° for 2hours, then at 20° for 2 hours. The mixture was added to water (500 ml)and extracted with ethyl acetate (2×200 ml). The aqueous phase was thenacidified to pill with conc. HCl and further extracted with ethylacetate (2×200 ml). The latter extracts were washed with water (2×200ml), dried (MgSO₄) and evaporated to give the title compound as a gum(8.6 g, 50.5%).

¹ H NMR (CDCl₃): δ 0.95 (d, 6H, CH₃), 2.08 (tq, 1H, CH), 4.25 (d, 2H,CH₂).

3. Preparation of Methyl 4-(4-Phenylbutoxy)benzoate

A solution of methyl 4-hydroxybenzoate (13.4 kg, 88 mol) in DMF (52 L)was added dropwise to a mixture of NaOMe (4.8 kg, 89 mol) and DMF (50 L)at room temperature under a gentle stream of nitrogen. The reactionmixture was heated at 60°-70° for 1 hr with stirring and then cooled toroom temperature. To this mixture was added dropwise a solution of4-phenylbutyl bromide (16.92 kg, 79.4 mol) in DMF (5 L). The resultingmixture was heated at 60°-70° for 1 hr with constant sting and cooled toroom temperature. After an addition of 1N-NaOH (110 L) was added, andthe product was extracted twice with ethyl acetate (50 L and 80 L). Theextracts were washed with 1N-NaOH (110 L) and saturated brine (20 L)successively, and then concentrated to dryness in vacuo to give thetitle compound in quantitative yield.

4. Preparation of 4-(4-Phenylbutoxy)benzoic Acid

To a solution of the compound from Example 3 in MeOH (50 L) was added3N-NaOH (46 L). The mixture was heated under reflux for 1.5 hrs. Upontermination of the reaction, the MeOH was removed by distillation invacuo. Ice-water (120 L) was added to the residue, and the neutralmaterials were extracted with ether (30 L×3). The combined etherealextracts were washed with 2N-NaOH (25 L). The aqueous layers werecombined and adjusted to pH 2-3 with concentrated HCl (16 L).Precipitated solids were collected by centrifugal filtration, washedwith water and dried by heating at 70°-80° under a stream of air toobtain the title compound, (17.67 kg, 65.4 mol, 82% yield from4-hydroxybenzoate).

5. Preparation of3-[4-(4-Phenylbutoxy)benzoylamino]-2-hydroxyacetophenone

To a solution of the compound from Example 4 (18.1 g, 67 mmol) in CH₂Cl₂ (45 ml) was added a catalytic amount of DMF (0.45 ml) followed bythionyl chloride (6.26 ml, 85.8 mmol) at room temperature under a streamof nitrogen. After reflux for 2 hr, the mixture was cooled to roomtemperature and was added to a solution of3'-amino-2'-hydroxyacetophenone hydrochloride (12 g, 64 mmol) andpyridine (15.5 ml , 192 mmol) in CH₂ C12 (90 ml) while maintaining thetemperature between 0°-3°. The mixture was stiffed at 0°-3° for 2 hr,and poured into 2N-HCl (200 ml). The aqueous layer was separated. Theproduct in aqueous layer was extracted twice with CH₂ C12 (150 ml and100 ml). The CH₂ C12 layers were combined, washed successively withwater, saturated NaHCO₃ (150 ml), and saturated brine (150 ml), driedover MgSO₄. The resulting solution was concentrated in vacuo until someof the crystals were precipitated. Ethyl acetate (150 ml) was added tothe residue, and the solution was concentrated in vacuo until about ahalf of the ethyl acetate was distilled out. The mixture was cooled toapproximately 0°. Precipitated crystals were collected by filtration anddried in vacuo to afford the title compound, (21.6 g, 53.6 mmol, 90%yield).

6. Preparation of2-[4-(4-Phenylbutoxy)benzoylamino]-6-[1,3-dioxo-3-(tetrazol-5-yl)propyl]phenol

Under a nitrogen atmosphere, potassium tert-butoxide (31.36 g, 0.28 mol)was dissolved in dry DMF (160 ml) by stirring. To the resulting solutionwere added the hydroxy acetophenone compound from Example 5 (16.12 g,0.04 mol) followed by 5-ethoxycarbonyl tetrazole from Example 1 (7.39 g,0.052 mol, 1.3 equiv.) at room temperature. The reaction temperaturerises to approximately 45°. The mixture was stirred for 3 hours at 40°(oil bath), then cooled to 30° and poured into cold 1N HCl (800 ml). Theresulting precipitate was filtered, washed with water (500 ml), and thendried at 70° in a fan oven to obtain the title compound (19.4 g, 97%).Purification was carried out using either of the following procedures.

Procedure 1: A stirred slurry of crude product (10 g)in ethyl acetate(150 ml) was heated at 60° for 2 hours. After cooling to roomtemperature, the mixture was transferred to a refrigerator and left for2 hours. The product was then filtered, washed with cold ethyl acetate(15 ml), and dried at 70° in a fan oven to afford purified product (8.5g, 85%).

Procedure 2: A stirred slurry of crude product (5 g) in acetone (50 ml)was heated under reflux for 2 hours. After cooling to room temperature,the mixture was transferred to a refrigerator and left for 2 hours. Theproduct was then filtered, washed with cold acetone (5-10 ml), and driedat 70° in a fan oven to afford purified product (4.1 g, 82%).

7. Preparation of4-Oxo-8-[4-(4-phenylbutoxy)benzyloyamino]-2-tetrazol-5-yl-4H-1-benzopyranhemihydrate

To a stirred slurry of purified product from Example 6 (7.984 g, 0.016mol) in methanol (72 ml) was added concentrated sulphuric acid (0.6 ml),and the reaction heated to reflux and stirred for 3 hours. The mixturewas allowed to cool to room temperature and then transferred to arefrigerator for 2 hours. The thick mixture was then filtered, washedwith cold methanol (40 ml) and water (90 ml) followed again by coldmethanol (30 ml). The product was dried at 70° in a fan oven and thenleft to stand for 24 hours at room temperature to afford the riflecompound (7.36 g, 96% ):

Examples 8 and 9

These two examples illustrate the `one-pot` procedure for thepreparation of compounds (I) from the intermediate compounds ofstructures (HI) and (IV).

8. Preparation of4-Oxo-8-[4-(4-phenylbutoxy)benzoylnmino]-2-tetrazol-5-yl-4H-1-benzopyranhemihydrate

To a stirred suspension of sodium methoxide (15 g, 0.28 mole) in dry THFunder a nitrogen atmosphere was added, in portions, thehydroxyacetophenone compound from example 5 (16 g, 0.04 mole) at about25° C. A solution of ethyl tetrazole-5-carboxylate from example 1 (7.3g, 0.05 mole) in THF was then added while maintaining the reactiontemperature at about 25° C. The reaction mixture was stirred at refluxfor about 100 minutes to ensure complete formation of the diketonecompound from example 6. Methanol was added to the reaction mixturefollowed by concentrated hydrochloric acid (28 ml, 0.34 mole), andsubsequent heating of the reaction mixture at reflux for about 2 hoursresulted in the formation of the title compound which crystallised outof solution. Afar cooling to about 20° C., the product was isolated byfiltration and washed with methanol. The isolated solid was purified byconversion to the sodium salt in methanol and reprecipitating the titlecompound with hydrochloric acid. The reprecipitated product was isolatedby filtration, washed with aqueous methanol, dried and then rehydratedat room temperature to give the title compound (18.56 g, 94%).

9. Preparation of4-Oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-tetrazol-5-yl-4H-1-benzopyran hemihydrate

To a stirred suspension of sodium methoxide (14.1 kg, 261 mole) in dryTHF under a nitrogen atmosphere was added, in portions, thehydroxyacetophenone compound from example 5 (15.0 kg, 37.2 mole) atabout 25° C. A solution of ethyl tetrazole-5-carboxylate from example 1(6.8 kg, 47.9 mole) in THF was then added while maintaining the reactiontemperature at about 25° C. The reaction mixture was stirred at refluxfor about 100 minutes to ensure complete formation of the diketonecompound from example 6. Methanol was added to the reaction mixturefollowed by concentrated hydrochloric acid (31.4 kg, 314 mole), andsubsequent heating of the reaction mixture at reflux for about 2 hoursresulted in the formation of the title compound which crystallised outof solution. After cooling to about 20° C., the product was isolated byfiltration and washed with methanol. The isolated solid was purified byconversion to the sodium salt in methanol and reprecipitating the titlecompound with hydrochloric acid. The reprecipitated product was isolatedby filtration, washed with aqueous methanol, dried and then rehydratedat room temperature to give the title compound (15.5 kg, 85%).

We claim:
 1. A process for preparing a compound of structure (I):##STR13## in which, R¹ is C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, ora group of structure: ##STR14## each of which may be substituted by oneor two substituents selected independently from the group consisting ofC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl or C₂₋₂₀ alkynyl, up to 5 carbon atom(s) ofwhich may be replaced independently by one or more radicals selectedfrom the group consisting of oxygen, sulphur, halogen, nitrogen,benzene, thiophene, naphthalene, a carbocyclic ring of from 4 to 7carbon atoms, carbonyl, carbonyloxy, hydroxy, carboxy, azido andnitro;R² is hydrogen or C₁₋₆ alkyl; R³ is hydrogen, halogen, hydroxy,nitro, a group of general formula --COOR⁴ (wherein R⁴ representshydrogen or C₁₋₆ alkyl), or C₁₋₆ alkyl, C₁₋₆ alkoxy or C₁₋₆ alkylthio; Ais a single bond or a methylene, ethylene, trimethylene, tetramethylene,vinylene, propenylene, butenylene, butadienylene or ethynylene groupoptionally being substituted by one, two or three C₁₋₁₀ alkyl and/orphenyl group(s); and X is oxygen or sulphur; or a salt, hydrate orsolvate thereof, which comprises cyclisation of a compound of structure(II) ##STR15## or a salt, hydrate or solvate thereof, in which R¹, R²,R³, A and X are as described for structure (I), and optionallythereafter forming a salt, hydrate or solvate thereof.
 2. A processaccording to claim 1 in which R¹ is ##STR16## A is a single bond, X isoxygen, R² is hydrogen and R³ is hydrogen.
 3. A process according toclaim 2 in which the cyclisation reaction is carried out in the presenceof hydrochloric acid in methanol/tetrahydrofuran as solvent.
 4. Acompound of structure (II): ##STR17## in which R¹, R², R³, A and X areas described for structure (I), or a salt, hydrate or solvate thereof.5.2-[4-(4-Phenylbutoxy)benzoylamino]-6-[1,3-dioxo-3-(tetrazol-5-yl)propyl]phenol.6. A process for preparing a compound of structure (II) which comprisesreaction of a compound of structure (III): ##STR18## in which R¹, R²,R³, A and X are as described for structure (I) in claim 1 with acompound of structure (IV) or a salt thereof: ##STR19## in which Z is anactivated leaving group.
 7. A process according to claim 6 in which, instructure (III), R¹ is ##STR20## A is a single bond, X is oxygen, R² ishydrogen and R³ is hydrogen.
 8. A process for preparing a compound ofstructure (IA): ##STR21## or a salt, hydrate or solvate thereof, whichcomprises reaction of a compound of structure (IIIA) with a compound ofstructure (IVA) or a salt thereof: ##STR22## followed by cyclisation ofthe intermediate compound of structure (IIA) ##STR23## or a salt,hydrate or solvate thereof, so formed.
 9. A process for preparing acompound of structure (IV): ##STR24## in which Z is a group R⁶ O inwhich R⁶ is C₁₋₆ alkyl, optionally substituted phenyl or optionallysubstituted phenyl C₁₋₆ alkyl, which comprises reaction oftetrazole-5-carboxylic acid disodium salt with the appropriate alkyl,aryl or arylalkyl haloformate.